Lung Cancer: Treatment and Survival.
Lung cancers are divided by histopathology into small cell lung cancers (˜15%) and NSCLC (˜85%) [1]. In 2009, 219,440 new cases are expected and 159,390 persons are projected to die from lung cancer in the United States [2]. Prevailing treatments have only limited success in lung cancer, particularly NSCLC, which becomes resistant to the drugs used for chemotherapy.
Radiotherapy, alone or in combination with surgery or chemotherapy, is useful in the management of NSCLC [3]. However, tumor radio-resistance, including intrinsic radio-resistance before treatments and acquired radio-resistance during radiotherapy, makes radiotherapy problematic for NSCLC [4]. There is no effective treatment available for advanced or metastatic NSCLC [5]. The global increase in lung cancer, together with its poor survival rate and resistance to classical chemotherapy, underscores the need for development of novel therapeutic strategies.
Oncolytic Virotherapy.
Oncolytic virotherapy is a novel strategy using viruses, either naturally occurring or genetically modified, to selectively target and destroy tumor cells while leaving surrounding non-malignant cells unharmed [6]. Our preliminary data show that ΔNS1 RSV replicates to a high titer in lung tumor cells, compared to the normal WI-38 diploid lung cells (FIG. 2B), and ΔNS1 RSV, not wt RSV, specifically kills lung cancer cells, but not normal WI-38 or NHBE cells (FIGS. 2A and 4A and Table 1). NS1 protein functions as an anti-apoptotic factor (FIG. 4A, B) and deletion of NS1 restores the apoptotic pathway in tumor cells.
TABLE 1ΔNS1 RSV preferentially kills human lung cancer cells.Virus (MOI = 10)ΔNS1 RSVwt RSVCellsCPE (24 h post-infection)WI-38 cells (Human normal embryonic lung−−fibrolast)NHBE cells (Normal human bronchial epithelial)−−H157 cells (erlotinib-resistant)++++−H480 cells (erlotinib- and dasatinib-resistant)++++−H1299 cells (erlotinib-resistant and p53−/−)++++−H441 cells (erlotinib- and dasatinib-resistant)+++−H368 cells+++−H1335 cells++++−A549 cells (erlotinib-resistant, dasatinib-++++−partially resistant)H23 cells (erlotinib- and dasatinib-resistant)+++−Note:−: no CPE;+++: CPE 50%-75%;++++: CPE >75%
Biology of RSV NS1 Protein.
RSV genome contains individual genes for ten viral proteins [7]. The transcription of RSV genes is polar, with the promoter-proximal genes being transcribed more frequently than the promoter-distal ones. The NS1 gene is promoter-proximally located at the 3′ end of the viral genome and therefore its mRNA is the most abundant of the RSV transcripts in a linear start-stop-restart mode [8] (FIG. 1). NS1 protein is referred to as nonstructural since it has not been detected in RSV particles. NS1 is exclusively found in RSV-infected cells. Our group, along with others, has found that NS1 can counter the type I IFN signaling during RSV infection [9, 10], implying that NS1 plays a direct role in inhibiting the host's innate immune response.
Mitochondria as Targets for Anticancer Agents.
Evasion from apoptotic cell death unregulated cell proliferation and eventual tumor development is one of the hallmarks of oncogenic cell transformation. We found that ΔNS1 RSV selectively induces apoptosis in tumor cells (FIG. 4), and also decreases mitochondrial ΔΨm and promotes mitochondrial swelling in A549 lung cancer cells, suggesting that mitochondrially-mediated apoptosis participates in the anti-tumor effect of ΔNS1 RSV.
RSV can be rendered nonpathogenic by mutating the NS1 gene so that it no longer inhibits IFN release, which attenuates viral infection in normal cells. However, these nonpathogenic RSV, ΔNS1 RSV, are still oncolytic because tumor cells are defective in their ability to produce and respond to IFN and, therefore, efficiently support the propagation of ΔNS1 RSV.